The effect of SRA intron-1 splicing on differential ratio of SRA-SRAP levels and on ER-mediated transcription in breast cancer cells

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Guo, Jimin
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The steroid receptor RNA activator gene (SRA1) generates two distinct entities. SRA RNA coactivates several NRs whereas SRA protein (SRAP) is suspected to regulate the activity of several transcription factors, including estrogen receptors (ER). Splicing of SRA intron-1 is the major event defining SRAP coding frame. Fully spliced, coding SRA and intron-1 retained, non-coding SRA coexist in breast cancer cells. The relative proportion between the two types of SRA RNA maintains a balance between two genetically linked entities, SRA and SRAP. In this study, a minigene model was used to demonstrate that the primary sequence of SRA exon-1-intron-1-exon-2 is sufficient for alternative splicing of SRA intron-1. In addition, a modified oligoribonucleotidic construct promotes SRA intron-1 retention in breast cancer cells. This oligoribonucleotide differentially alters estradiol-induced transcription of ER regulated genes. Together, results presented herein demonstrate that the SRA-SRAP balance, which can be artificially modified by targeting alternative splicing of SRA intron-1, might be a new critical target to treat breast cancer patients.
steroid receptor RNA activator, estrogen receptor, alternative splicing, breast cancer